Electrical Spinal Stimulation Research Articles

Acute neuromodulation restores spinally-induced motor responses after severe spinal cord injury

Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level. Repetitive DS delivery restored the spinally-evoked motor EMG responses that were previously suppressed by a calibrated spinal cord contusion. Sham experiments without DS delivery did not allow any spontaneous recovery. Thus, DS uniquely provides the potential for a greater long-term functional recovery after paralysis.

A Device for the Rehabilitation Therapy of Patients with Motor Pathology Using Mechanotherapy, Transcutaneous Electrical Stimulation of the Spinal Cord, and Biological Feedback

A device − Biokin − for the rehabilitation of patients with neurological motor impairments was developed, with the capacity to provide mechanotherapy in combination with transcutaneous electrical stimulation of the spinal cord and biological feedback. The Biokin device includes a mechanical unit for moving the patient’s lower limbs, a Biostim-5 five-channel stimulator for transcutaneous spinal electrical stimulation, a biological feedback unit, and a control and switching unit; the system is controlled by computer. The device can be used in therapeutic, therapeutic-prophylactic, and scientific research facilities or at home.

Chronic, closed‐loop, cervical epidural stimulation elicits plasticity in diaphragm motor output and upregulates spinal neurotrophic factor gene expression

Electrical spinal stimulation after spinal cord injury (SCI) improves functional outcomes. However, there's an unmet need to understand if epidural stimulation has a lasting impact on motor systems in people with chronic SCI. We developed a closed‐loop stimulation protocol (endogenous respiratory output from diaphragm EMG‐triggered spinal stimulation with bilateral stim electrodes at C4) in freely behaving rats. We hypothesized that long‐term (20 h/day, 4 d), closed‐loop epidural stimulation elicits plasticity in diaphragm EMG. Since neurotrophic factor expression is upregulated after spinal stimulation in other systems, and is associated with mechanisms of spinal respiratory motor plasticity, we hypothesized that stimulation upregulates neurotrophic factor gene expression in the cervical spinal cord. Four rat groups were studied: 1) C2 hemisection (C2HS) + stim (n = 3); 2) C2HS + no stim (n = 3); 3) no injury + stim (n = 2); and 4) sham controls (n = 2). Increased current during motor evoked potential testing increased area under the curve (AUC) of the stimulus‐triggered average in all rats (range: 50–750mA or max tolerated; ~0.5Hz inspiratory‐triggered). However, after 4 d of stim, a dramatic AUC potentiation was observed in 2 of 3 C2HS rats (667% and 239% increase from 1d – 4d, 520mA vs. 6% in the non‐responder) in ipsilesional diaphragm. Contralesional AUC was also potentiated (565% and 199% increase from 1d‐4d, 520mA vs. −6% in the non‐responder). Ipsilesional peak‐to‐peak amplitude increased after stimulation (2.9mV at 4d vs. 0.5mV at 1d) with additional peaks appearing in longer time domains, suggesting potential for interneuronal recruitment. qPCR neurotrophic factor and receptor mRNA (VEGFA & VEGFR2, BDNF & TrkB, NT3 & TrkC) revealed that stim after injury upregulated VEGFA (1.06 ± 0.77 fold vs. 0.948 in injury only) and BDNF (1.53 ± 0.35 fold vs. 1.00 in injury only) in C3–C5 ventral spinal cord. Dorsal spinal VEGFA, BDNF and TrkB were downregulated after injury in C1–C2 (0.42 fold vs. 1.00 in sham; 0.43 fold vs. 1.01 in sham; and 0.56 fold vs 1.00 in sham, respectively). However, stim post‐injury partially restored expression of VEGFA (0.60 ± 0.02 fold), BDNF (0.64 ± 0.02 fold) and TrkB (0.74 ± 0.06 fold). This was surprising as the stimulation site is several segments below the injury. Finally, in dorsal C1–C3, C2HS downregulated both NT3 and TrkC after injury (NT3: 0.43 fold vs.1.00 in sham; TrkC: 0.43 fold vs. 1.01 in sham) with a partial recovery of NT3 (0.64 fold ± 0.02) and TrkC (0.64 fold ± 0.02) post‐stim. In C3–C5 ventral horn, stim upregulated TrkC mRNA (1.01 ± 0.05 vs. 0.95), suggesting a possible substrate for axonal growth. Collectively these preliminary results demonstrate the first known evidence of spinal respiratory plasticity associated with long‐term spinal stimulation in an awake, freely‐behaving animal. Results from gene expression assays lay the groundwork for essential mechanistic studies of epidural stimulation.Support or Funding InformationCraig Nielsen FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Self-Assisted Standing Enabled by Non-Invasive Spinal Stimulation after Spinal Cord Injury.

Neuromodulation of spinal networks can improve motor control after spinal cord injury (SCI). The objectives of this study were to (1) determine whether individuals with chronic paralysis can stand with the aid of non-invasive electrical spinal stimulation with their knees and hips extended without trainer assistance, and (2) investigate whether postural control can be further improved following repeated sessions of stand training. Using a double-blind, balanced, within-subject cross-over, and sham-controlled study design, 15 individuals with SCI of various severity received transcutaneous electrical spinal stimulation to regain self-assisted standing. The primary outcomes included qualitative comparison of need of external assistance for knee and hip extension provided by trainers during standing without and in the presence of stimulation in the same participants, as well as quantitative measures, such as the level of knee assistance and amount of time spent standing without trainer assistance. None of the participants could stand unassisted without stimulation or in the presence of sham stimulation. With stimulation all participants could maintain upright standing with minimum and some (n = 7) without external assistance applied to the knees or hips, using their hands for upper body balance as needed. Quality of balance control was practice-dependent, and improved with subsequent training. During self-initiated body-weight displacements in standing enabled by spinal stimulation, high levels of leg muscle activity emerged, and depended on the amount of muscle loading. Our findings indicate that the lumbosacral spinal networks can be modulated transcutaneously using electrical spinal stimulation to facilitate self-assisted standing after chronic motor and sensory complete paralysis.

Electrical Spinal Stimulation, and Imagining of Lower Limb Movements to Modulate Brain-Spinal Connectomes That Control Locomotor-Like Behavior.

Neuronal control of stepping movement in healthy human is based on integration between brain, spinal neuronal networks, and sensory signals. It is generally recognized that there are continuously occurring adjustments in the physiological states of supraspinal centers during all routines movements. For example, visual as well as all other sources of information regarding the subject's environment. These multimodal inputs to the brain normally play an important role in providing a feedforward source of control. We propose that the brain routinely uses these continuously updated assessments of the environment to provide additional feedforward messages to the spinal networks, which provides a synergistic feedforwardness for the brain and spinal cord. We tested this hypothesis in 8 non-injured individuals placed in gravity neutral position with the lower limbs extended beyond the edge of the table, but supported vertically, to facilitate rhythmic stepping. The experiment was performed while visualizing on the monitor a stick figure mimicking bilateral stepping or being motionless. Non-invasive electrical stimulation was used to neuromodulate a wide range of excitabilities of the lumbosacral spinal segments that would trigger rhythmic stepping movements. We observed that at the same intensity level of transcutaneous electrical spinal cord stimulation (tSCS), the presence or absence of visualizing a stepping-like movement of a stick figure immediately initiated or terminated the tSCS-induced rhythmic stepping motion, respectively. We also demonstrated that during both voluntary and imagined stepping, the motor potentials in leg muscles were facilitated when evoked cortically, using transcranial magnetic stimulation (TMS), and inhibited when evoked spinally, using tSCS. These data suggest that the ongoing assessment of the environment within the supraspinal centers that play a role in planning a movement can routinely modulate the physiological state of spinal networks that further facilitates a synergistic neuromodulation of the brain and spinal cord in preparing for movements.

Non-invasive Neuromodulation of Spinal Cord Restores Lower Urinary Tract Function After Paralysis.

It is commonly assumed that restoration of locomotion is the ultimate goal after spinal cord injury (SCI). However, lower urinary tract (LUT) dysfunction is universal among SCI patients and significantly impacts their health and quality of life. Micturition is a neurologically complex behavior that depends on intact sensory and motor innervation. SCI disrupts both motor and sensory function and leads to marked abnormalities in urine storage and emptying. Current therapies for LUT dysfunction after SCI focus on preventing complications and managing symptoms rather than restoring function. In this study, we demonstrate that Transcutaneous Electrical Spinal Stimulation for LUT functional Augmentation (TESSLA), a non-invasive neuromodulatory technique, can reengage the spinal circuits' active in LUT function and normalize bladder and urethral sphincter function in individuals with SCI. Specifically, TESSLA reduced detrusor overactivity (DO), decreased detrusor-sphincter dyssynergia (DSD), increased bladder capacity and enabled voiding. TESSLA may represent a novel approach to transform the intrinsic spinal networks to a more functionally physiological state. Each of these features has significant clinical implications. Improvement and restoration of LUT function after SCI stand to significantly benefit patients by improving their quality of life and reducing the risk of incontinence, kidney injury and urinary tract infection, all the while lowering healthcare costs.

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of \u03b12-adrenoceptors and 5-HT1 receptors

BackgroundDihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow.MethodsPithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure.ResultsDHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses.ConclusionDHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance.

Application of neurophysiology in electrical cervical spinal cord stimulation for persistent vegetative state

Objective To investigate the correlation between the overall scores of multimodal neurophysiological methods [electroencephalography (EEG), brainstem auditory evoked potential (BAEP), somatosensory evoked potential (SEP)] and therapeutic effect of cervical spinal cord stimulation (cSCS) in patients with persistent vegetative state (PVS) resulting from non-traumatic brain injury. Methods A retrospective analysis was conducted on the clinical data, neurophysiological scores and 1-year outcomes of 48 PVS patients who underwent treatment of cSCS (study group) at Department of Neurosurgery, Daqing Oilfield General Hospital from January 2010 to February 2017. The results were compared with the clinical data and outcomes of 50 patients undergoing conservative resuscitating treatment (control group) during the same period. We investigated the relationship between multimodal neurophysiological scores and therapeutic effect of cSCS treatment by Spearman rank correlation analysis in the study group. Results In the study group, 18 cases (37.5%) were resuscitated from PVS, 11 cases (22.9%) reported obvious therapeutic effect. In the control group, 3 cases (6.0%) were resuscitated from PVS, 4 cases (8.0%) had obvious therapetuic effect at 1 year post treatment. The treatment effect was significantly different between study group (R=0.6077) and control group (R=0.3966) by Ridit analysis (P<0.05). The cSCS treatment demonstrated better therapeutic effect than conservative resuscitating treatment. The Spearman rank correlation analysis showed that there was a positive correlation between the cSCS efficacy and neurophysiological scores (rs=0.854, P<0.05), i. e., higher overall neurophysiological scores indicated better therapeutic effect of cSCS. Conclusions (1) The cSCS awakening technology could promote neurological rehabilitation, improve the awakening ratio in PVS patients and facilitate early wake-up of PVS patients. (2) There is a positive correlation between multimodal neurophysiological scores and therapeutic effect of cSCS treatment. Multimodal neurophysiological scores play an important role in helping doctor choose cSCS awakening technology in clinical practice. Key words: Persistent vegetative state; Electrophysiology; Cervical spinal cord stimulation; Multimodal neurophysiology

Spinal and sensory neuromodulation of spinal neuronal networks in humans

The present experiments were designed to gain additionally insight into how the spinal networks process direct spinal stimulation and peripheral sensory inputs to control posture and locomotor movements. We have developed a plantar pressure stimulation system that can deliver naturalistic postural and gait-related patterns of pressure to the soles of the feet to simulate standing and walking, thereby activating and/or modulating the automated spinal circuitry responsible for standing and locomotion. In the present study we compare the patterns of activation among selected motor pools and the kinematic consequences of these activation patterns in response to patterned heel-to-toe mechanical stimulation of the soles of the feet, and/or transcutaneous electrical spinal stimulation, for postural and locomotion regulation. The studies were performed in healthy individuals (n = 12) as well as in subjects (n = 2) with motor complete spinal cord injury. We found that plantar pressure stimulation and/or spinal stimulation can effectively facilitate locomotor output in the subjects placed with their legs in gravity neutral position. We have shown synergistic effects of combining sensory and spinal cord stimulation, suggesting that the two networks are different, but complementary. Also we provide evidence that plantar stimulation could serve as a novel neuro-rehabilitation tool alone or as part of a multi-modal approach to restoring motor function after complete paralysis due to SCI.

Epidural and transcutaneous spinal electrical stimulation for restoration of movement after incomplete and complete spinal cord injury.

The Purpose of this review is to outline and explain the therapeutic use of electrical spinal cord stimulation (SCS) for modification of spinal motor output. Central functional stimulation provides afferent input to posterior root neurons and is applied to improve volitional movements, posture and their endurance, control spasticity, and improve bladder function or perfusion in the lower limbs. Clinical accomplishments strongly depend on each individual's physiological state and specific methodical adaptation to that physiological state. Effectiveness of this neuromodulory technique for changing motor control after spinal cord injury (SCI) continues to be explored along with the underlying mechanisms of its effect in people with complete and incomplete spinal cord injuries. There are extensive studies of tonic and rhythmical activity elicited from the lumbar cord as well as data demonstrating augmentation of residual volitional activity. Recent studies have focused on verifying if and how SCS can modify features of neurocontrol in ambulatory spinal cord patients. In this review, we emphasize recent publications of research revealing that SCS can substitute for the reduced brain drive for control of excitability in people with SCI. Artificially replacing diminished or lost brain control over the spinal cord has limitations. A fundamental requirement for successful SCS application is analysis of each individual's residual postinjury neural function. This will allow a better understanding of the physiological interactions between SCS and spinal cord motor control below injury and provide criteria for its application. Finally, the publication of both successful and failed applications of SCS will be crucial for gaining future progress.

Nonpharmacological Treatment Approach to Pain

Chronic pain has various forms such as inflammatory pain, visceral pain, headache, disk-related pain, neuropathic pain, cancer pain. Although the biological basis of chronic pain is related to vulnerability, it continues with behavioral and psychological components. In the context of multimodal interventions, interventions other than systemic pharmacologic treatments for chronic pain are also present. Besides interventional approaches; there are several noninvasive options including cognitive behavioral therapy, biofeedback, relaxation therapy, physical therapy, thermal applications, spinal cord stimulation and transcutaneous electrical stimulation. The neuroscientific approach to pain can only be achieved by combining physical and mental components of the pain with neuroscience

The 5-HT 1 receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: Further involvement of 5-HT 1F, but not 5-HT 1A or 5-HT 1D, subtypes

We have previously shown that 5-HT 1B receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT 1 receptors comprise 5-HT 1A, 5-HT 1B, 5-HT 1D and 5-HT 1F functional subtypes, this study has further investigated the role of 5-HT 1A, 5-HT 1D and 5-HT 1F receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT 1 receptor agonists. Then electrical spinal stimulation (T 9–T 12) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT 1A receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT 1A/1B/1D/1F), indorenate (5-HT 1A), PNU-142633 (5-HT 1D) or LY344864 (5-HT 1F), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 μg/kg (but not 100 μg/kg) GR127935 (5-HT 1A/1B/1D/1F) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 μg/kg SB224289 (5-HT 1B) or BRL15572 (5-HT 1D) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289 + BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 μg/kg WAY100635 (5-HT 1A) failed to block the inhibition to indorenate. These results suggest that 5-HT 1F, but not 5-HT 1A or 5-HT 1D, receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT 1F receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.

Spinal electrical stimulation for the management of refractory angina pectoris: Literature review

Introducción: La angina es una condición médica muy común que limita la actividad diaria y deteriora la calidad de vida. Existe un grupo de pacientes con angina de pecho crónica refractaria que no son candidatos a revascularización quirúrgica o percutánea y que a pesar de un manejo médico óptimo continúan experimentando severos episodios de angina. La estimulación eléctrica espinal con un neuromodulador es una alternativa para el manejo de estos pacientes. Objetivo: Se realizó una revisión sobre la estimulación eléctrica espinal para el manejo de la angina, su mecanismo de acción, beneficios y costo-efectividad. Material y método: Se realizó una búsqueda en MedLine, según la metodología Cochrane, de artículos publicados desde enero de 1980 a enero del 2007 usando los términos “spinal cord stimulation”. De esta búsqueda se seleccionaron los artículos considerados relevantes por parte de los autores. Conclusiones: El efecto anti isquémico de la estimulación eléctrica espinal reduce los episodios de angina de pecho, mejora la calidad de vida y la tolerancia al ejercicio, disminuye la estancia hospitalaria y retarda la aparición de los signos de la isquemia.

Management of Spasticity After Spinal Cord Injury: Current Techniques and Future Directions

Spasticity, resulting in involuntary and sustained contractions of muscles, may evolve in patients with stroke, cerebral palsy, multiple sclerosis, brain injury, and spinal cord injury (SCI). The authors critically review the neural mechanisms that may contribute to spasticity after SCI and assess their likely degree of involvement and relative significance to its pathophysiology. Experimental data from patients and animal models of spasticity as well as computer simulations are evaluated. The current clinical methods used for the management of spasticity and the pharmacological actions of drugs are discussed in relation to their effects on spinal mechanisms. Critical assessment of experimental findings indicates that increased excitability of both motoneurons and interneurons plays a crucial role in pathophysiology of spasticity. New interventions, including forms of spinal electrical stimulation to suppress increased neuronal excitability, may reduce the severity of spasticity and its complications.

Poster 240: Electrical Spinal Stimulation in the Treatment of Refractory Angina

Poster 240: Electrical Spinal Stimulation in the Treatment of Refractory Angina

Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings.

Although Mg2+ contributes to blood pressure regulation partly in terms of vasodilator action, its sympatholytic effect may also play an important role to control blood pressure. Thus, in the present study, we investigated the effect of Mg2+ on sympathetic tone and blood pressure. We studied its actions on the blood pressure response to hydralazine, a direct vasodilator, in conscious spontaneously hypertensive rats (SHRs), and to electrical stimulation in the pithed Sprague-Dawley rat; catecholamine release by peripheral sympathetic nerve endings; and the N-type Ca2+ channels of cultured neural cells. Intravenous Mg2+ infusion (MgSO4: 3x10(-6) mol/kg body weight/min) induced the greater hypotensive response to hydralazine with attenuated reflex tachycardia in SHRs. In pithed rats, Mg2+ infusion significantly attenuated the blood pressure elevation (2+/-2 mm Hg versus 27+/-6 mm Hg, P<0.01) in response to spinal electrical stimulation. In the perfused mesenteric arteries system, norepinephrine release was significantly attenuated (51+/-2%, P<0.01) by high Mg2+ concentration solution (4.8 mmol/L) compared with normal Mg2+ solution (1.2 mmol/L). When we applied the perforated whole-cell patch clamp method to nerve growth factor-treated PC12 cells, Mg2+ blocked voltage-gated Ca2+ currents in a concentration-dependent manner. The majority of the voltage-gated Ca2+ currents were carried through N-type channels, followed by L-type channels. Mg2+ blocked both of these channels. These findings suggest that Mg2+ blocks mainly N-type Ca2+ channels at nerve endings, and thus inhibits norepinephrine release, which decreases blood pressure independent of its direct vasodilating action.

Mechanisms of Cortical Reorganization in Lower-Limb Amputees

The human motor system undergoes reorganization after amputation, but the site of motor reorganization and the mechanisms involved are unknown. We studied the site and mechanisms of motor reorganization in 16 subjects with traumatic lower-limb amputation. Stimulation at different levels in the CNS was used to determine the site of reorganization. The mechanisms involved were evaluated by measuring the thresholds for transcranial magnetic stimulation (TMS) and by testing intracortical inhibition and facilitation. With TMS, the threshold for muscle activation on the amputated side was lower than that of the intact side, but with transcranial electrical stimulation there was no difference in motor threshold between the two sides. TMS at the maximal output of the stimulator activated a higher percentage of the motor neuron pool (%MNP) on the amputated side than on the intact side. The %MNP activated by spinal electrical stimulation was similar on the two sides. Paired TMS study showed significantly less intracortical inhibition on the amputated side. Our findings suggest that motor reorganization after lower-limb amputation occurs predominately at the cortical level. The mechanisms involved are likely to include reduction of GABAergic inhibition.

Evidence for purinergic neurotransmission in the urinary bladder of pithed rats

The purpose of this study was to investigate the contribution of adenosine-5′-triphosphate (ATP) to segmental (L6-S2) spinal electrical stimulation evoked increases in intra-vesical pressure in pithed rats. Exogenous ATP and substance P produced dose-dependent increases in intra-vesical pressure (ED 10 mmHg (dose required to elicit 10 mmHg increase in intra-vesical pressure)=1.7 mg/kg and 1.1 μg/kg, i.v., respectively). Desensitisation (or antagonism) of P 2x purinoceptors with α, β-methylene ATP ( α, β-meATP; 30 μg/kg per min, i.v.) or pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 10 mg/kg, i.v.) significantly ( p<0.05) antagonized the intra-vesical pressure responses to ATP (>8 and 3.6-fold increase in ED 10 mmHg, respectively) but had no significant effect on intra-vesical pressure responses to substance P. Spinal stimulation evoked frequency-dependent increases in intra-vesical pressure (EF 20 mmHg (frequency required to produce 20 mmHg increase in intra-vesical pressure)=3.4 Hz). Blockade of muscarinic cholinoceptors and adrenoceptors with atropine (3 mg/kg, i.v.), propranolol (3 mg/kg, i.v.) and phentolamine (10 mg/kg, i.v.) produced marginal attenuation of the intra-vesical pressure responses to spinal stimulation indicating a major non-adrenergic non-cholinergic (NANC) component in the overall response. The NANC responses were significantly ( p<0.05) antagonized by α, β-meATP (30 μg/kg per min, i.v.) and PPADS (10 mg/kg, i.v.) (>2.6-fold increase in EF 20 mmHg), consistent with involvement of a purinergic neurotransmitter, presumably ATP. Comparative studies in young (4–6 months) and old (21–23 months) Fischer rats revealed no age-dependent changes in the relative contribution of the cholinergic and purinergic systems, with the latter being the dominant one. These findings suggest that purinergic neurotransmission, presumably mediated by ATP acting via P 2x purinoceptors, represents a major component of excitatory innervation to the urinary bladder in pithed rats.

Spinal electrical stimulation for intractable angina—long-term clinical outcome and safety

Spinal cord electrical stimulation is an alternative therapy for patients with chronic pain syndromes including angina. Although it has been shown to produce symptomatic relief and reduce ischaemia, doubts remain about its long-term safety. We report here for the first time the results of a follow-up study over a period of 62 months, mean 45 months (range 21-62), of 23 patients who had stimulator units implanted for intractable angina unresponsive to standard therapy. Symptomatic improvement was good and persisted in the majority with a mean (SD) change of NYHA grade from 3.1 (0.8) pre-operatively to 2.0 (0.9) (P < 0.01) immediately after operation and 2.1 (1.07) at the latest follow-up. GTN consumption fell markedly. Mean (SEM) treadmill exercise time increased from 407 (45) s with the stimulator off to 499 (46) s with the stimulator on (P < 0.01). Forty-eight hour ST segment monitoring in those with bipolar leads showed a reduction of total number and duration of ischaemic episodes. There were three deaths, none of which were sudden or unexplained and this mortality rate is acceptable for such a group of patients. Two patients had a myocardial infarction, which was associated with typical pain and not masked by the treatment. Complications related to earlier lead designs were frequent. This study confirms that spinal electrical stimulation is an effective and safe form of alternative therapy for the occasional patient whose angina is unresponsive to standard therapies.

Central motor conduction in human chronic Chagas' disease.

The possible involvement of spinal alpha motor neurons, dorsal root ganglia and sensory fibers in human chronic Chagas' disease was previously demonstrated. More recently neuropsychological and sensory evoked potentials studies suggest the existence of central nervous system abnormalities in these patients. We assessed the state of central motor pathways in 46 patients with chronic Chagas' disease and 30 healthy volunteers by means of percutaneous cortical and spinal electrical stimulation. No significative slowness in pyramidal tracts (PT) conduction was found when comparing both groups. Neither any individual patient exhibited abnormally delayed PT conduction values beyond the upper normal limit of the healthy volunteers. These results suggest that, in contrast with other neural systems, the large myelinated PT fibers are usually spared in human chronic Chagas' disease.